Cancer is one of the main diseases of the 21st century causing 13% of all deaths. While there are several chemicals that can affect rapidly dividing cancer cells, most of these chemicals are toxic with adverse side effects.
Cancer is expected to be the leading cause of death worldwide in the near future. Tumor cells exploit various signaling molecules to promote their growth, invasion and metastasis. A clear understanding of the mechanisms of actions of these molecules in malignancy will provide new insights into therapeutic interventions.
In response to stresses in the tumor microenvironment, such as hypoxia and inflammation, tumor cells exploit various signaling molecules to sustain and promote their growth, invasiveness and metastasis. Aggressive tumor metastasis and invasiveness is the main cause of mortality in cancer patients. The constitutive activation of intracellular signaling by these molecules in tumor cells causes changes in cellular functions, including increased proliferation and the ability of cells to grow outside their original confined milieu, leading to metastasis. Among these changes, the loss of dependence on integrin-mediated extracellular matrix contact for growth, or anoikis resistance, is an essential feature of tumor cells, yet how it is acquired remains an unsolved problem in cancer biology.
Although low levels of reactive oxygen species (ROS) regulate cellular signaling and play an important role in normal cell proliferation, recent studies show that tumors exhibit an excessive amount or persistent elevation of ROS (specifically the superoxide anion O2−) and utilize a redox-based mechanism to evade death by anoikis Previous studies have indicated that ROS are involved in tumor initiation, progression and maintenance. Furthermore, deregulated ROS production is also associated with an invasive tumor phenotype. Oncogenic and mitogenic Ras activity is superoxide-dependent, and a sustained increase in ROS following the overexpression of Mox1 (the catalytic subunit of NADPH oxidase) leads to cell transformation and aggressive tumor metastasis. Elevated production of ROS following activation of the c-Met proto-oncogene leads to cell transformation and malignant growth, and Rac-dependent redox signals increase the secretion of metalloproteases and induce the epithelial-mesenchymal transition, which are two key features of invasive cancers. Thus, a clear understanding of the underlying redox-based anoikis escape mechanism and its connection to malignancy will provide new insights into therapeutic interventions.
Anoikis resistance, a hallmark of tumor malignancies, is an integrin-dependent process. Reactive oxygen species (ROS) generated due to intergrin engagement oxidizes and activates Src, which stimulates the ERK and Akt pro-survival pathways. Both pathways regulate the subcellular location or stability of BH3-only apoptotic proteins (eg Bad and Bim), essential for executing anoikis Resistance to anoikis has been suggested to be a prerequisite for cancer cells to metastasize. The mechanism by which invading tumor cells survive the anoikis process remains largely unknown.
Angiopoietin-like protein 4 (ANGPTL4) are secreted proteins mainly expressed in liver that have been demonstrated to regulate triglyceride metabolism by inhibiting the lipolysis of triglyceride-rich lipoproteins. Experimental results show that ANGPTL4 function to regulate circulating triglyceride levels during different nutritional states and therefore play a role in lipid metabolism during feeding/fasting through differential inhibition of Lipoprotein lipase (LPL). The N-terminal domain of Angiopoietin-like proteins has been shown to play an active role in lipid metabolism. Using deletion mutants, it was demonstrated that the N-terminal domain containing fragment—(17-207) and not the C-terminal fibrinogen-like domain containing fragment—(207-460) increased the plasma triglyceride levels in mice. ANGPTL4 has been identified as a novel paracrine and, possibly, endocrine regulator of lipid metabolism and a target of peroxisome proliferators-activated receptors (PPARs). It is expressed in numerous cell types, such as adipocytes and hepatocytes, and is upregulated after fasting and hypoxia. Importantly, ANGPTL4 undergoes proteolytic processing to release its C-terminal fibrinogen-like domain (cANGPTL4), which circulates as a monomer yet whose function remains unclear. The N-terminal coiled-coil domain of ANGPTL4 (nANGPTL4) mediates the oligomerization of ANGPTL4 and binds to lipoprotein lipase to modulate lipoprotein metabolism. It is now established that the nANGPTL4 mediates its oligomerization and binds to lipoprotein lipase to modulate lipoprotein metabolism. In contrast, cANGPTL4 exists as a monomer, and its function still remains unknown.
ANGPTL4 was recently linked to tumor progression. The angiopoietin-like 4 protein (ANGPTL4) has well-studied roles in metabolism, yet its role in cancer biology remains undefined as a predictive gene for breast cancer metastasis, where it disrupts endothelial integrity. However, whether ANGPTL4 promotes or inhibits vascular permeability, and thus cancer metastasis remains controversial. There is apparently conflicting results as to the underlying mechanism of ANGPTL4 activity in tumor cells that have not been clarified, hampering our understanding of its precise role in cancer metastasis. The role of ANGPTL4 in cancer biology remains unesertianed.